Adipocytes impact on gastric cancer progression: Prognostic insights and molecular features.

BACKGROUND: Adipocytes, especially adipocytes within tumor tissue known as cancer-associated adipocytes, have been increasingly recognized for their pivotal role in the tumor microenvironment of gastric cancer (GC). Their influence on tumor progression and patient prognosis has sparked significant interest in recent research. The main objectives of this study were to investigate adipocyte infiltration, assess its correlation with clinical pathological features, develop a prognostic prediction model based on independent prognostic factors, evaluate the impact of adipocytes on immune cell infiltration and tumor invasiveness in GC, and identify and validate genes associated with high adipocyte expression, exploring their potential diagnostic and prognostic value. AIM: To explore the relationship between increased adipocytes within tumor tissue and prognosis in GC patients as well as the associated mechanisms and potential biomarkers, using public databases and clinical data. METHODS: Using mRNA microarray datasets from the Gene Expression Omnibus database and clinical samples from Jiangsu Provincial Hospital, survival and regression analyses were conducted to determine the relevant prognostic factors in GC. Feature gene selection was performed using least absolute shrinkage and selection operator and support vector machine recursive feature elimination algorithms, followed by differential gene expression analysis, gene ontology, pathway analysis, and Gene Set Enrichment Analysis. Immune cell infiltration was analyzed using the CIBERSORT algorithm. RESULTS: Tumor adipocyte infiltration correlated with poor prognosis in GC, leading to the development of a highly accurate and discriminative prognostic prediction model. Key genes, ADH1B, SFRP1, PLAC9, and FABP4, were identified as associated with high adipocyte expression in GC. The diagnostic and prognostic potential of these identified genes was validated using independent datasets. Downregulation of immune cells was observed in GC with high adipocyte expression. CONCLUSION: GC with high intratumoral adipocyte expression demonstrated aggressive tumor biology and a poorer prognosis. The genes ADH1B, SFRP1, PLAC9, and FABP4 have been identified as holding diagnostic and prognostic significance in GC. These findings strongly support the use of adipocyte expression as a valuable indicator of tumor invasiveness and anticipated patient outcomes in GC.

Inhibition of the p62-Nrf2-GPX4 Pathway Confers Sensitivity to Butachlor-Induced Splenic Macrophage Ferroptosis.

Butachlor is widely used in agriculture around the world and therefore poses environmental and public health hazards due to persistent and poor biodegradability. Ferroptosis is a type of iron-mediated cell death controlled by glutathione (GSH) and GPX4 inhibition. P62 is an essential autophagy adaptor that regulates Keap1 to activate nuclear factor erythroid 2-related factor 2 (Nrf2), which effectively suppresses lipid peroxidation, thereby relieving ferroptosis. Here, we found that butachlor caused changes in splenic macrophage structure, especially impaired mitochondrial morphology with disordered structure, which is suggestive of the occurrence of ferroptosis. This was further confirmed by the detection of iron metabolism, the GSH system, and lipid peroxidation. Mechanistically, butachlor suppressed the protein level of p62 and promoted Keap1-mediated degradation of Nrf2, which results in decreased GPX4 expression and accelerated splenic macrophage ferroptosis. These findings suggest that targeting the p62-Nrf2-GPX4 signaling axis may be a promising strategy for treating inflammatory diseases.

Risk factors, prognostic factors, and nomograms for distant metastasis in patients with diagnosed duodenal cancer: A population-based study.

BACKGROUND: Duodenal cancer is one of the most common subtypes of small intestinal cancer, and distant metastasis (DM) in this type of cancer still leads to poor prognosis. Although nomograms have recently been used in tumor areas, no studies have focused on the diagnostic and prognostic evaluation of DM in patients with primary duodenal cancer. AIM: To develop and evaluate nomograms for predicting the risk of DM and personalized prognosis in patients with duodenal cancer. METHODS: Data on duodenal cancer patients diagnosed between 2010 and 2019 were extracted from the Surveillance, Epidemiology, and End Results database. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for DM in patients with duodenal cancer, and univariate and multivariate Cox proportional hazards regression analyses were used to determine independent prognostic factors in duodenal cancer patients with DM. Two novel nomograms were established, and the results were evaluated by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: A total of 2603 patients with duodenal cancer were included, of whom 457 cases (17.56%) had DM at the time of diagnosis. Logistic analysis revealed independent risk factors for DM in duodenal cancer patients, including gender, grade, tumor size, T stage, and N stage (P < 0.05). Univariate and multivariate COX analyses further identified independent prognostic factors for duodenal cancer patients with DM, including age, histological type, T stage, tumor grade, tumor size, bone metastasis, chemotherapy, and surgery (P < 0.05). The accuracy of the nomograms was validated in the training set, validation set, and expanded testing set using ROC curves, calibration curves, and DCA curves. The results of Kaplan-Meier survival curves (P < 0.001) indicated that both nomograms accurately predicted the occurrence and prognosis of DM in patients with duodenal cancer. CONCLUSION: The two nomograms are expected as effective tools for predicting DM risk in duodenal cancer patients and offering personalized prognosis predictions for those with DM, potentially enhancing clinical decision-making.

Apical papilla stem cell-derived exosomes regulate lipid metabolism and alleviate inflammation in the MCD-induced mouse NASH model.

Stem cells from the apical papilla(SCAPs) exhibit remarkable tissue repair capabilities, demonstrate anti-inflammatory and pro-angiogenic effects, positioning them as promising assets in the realm of regenerative medicine. Recently, the focus has shifted towards exosomes derived from stem cells, perceived as safer alternatives while retaining comparable physiological functions. This study delves into the therapeutic implications of exosomes derived from SCAPs in the methionine-choline-deficient (MCD) diet-induced mice non-alcoholic steatohepatitis (NASH) model. We extracted exosomes from SCAPs. During the last two weeks of the MCD diet, mice were intravenously administered SCAPs-derived exosomes at two distinct concentrations (50 µg/mouse and 100 µg/mouse) biweekly. Thorough examinations of physiological and biochemical indicators were performed to meticulously evaluate the impact of exosomes derived from SCAPs on the advancement of NASH in mice induced by MCD diet. This findings revealed significant reductions in body weight loss and liver damage induced by the MCD diet following exosomes treatment. Moreover, hepatic fat accumulation was notably alleviated. Mechanistically, the treatment with exosomes led to an upregulation of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) levels in the liver, enhancing hepatic fatty acid oxidation and transporter gene expression while inhibiting genes associated with fatty acid synthesis. Additionally, exosomes treatment increased the transcription levels of key liver mitochondrial marker proteins and the essential mitochondrial biogenesis factor. Furthermore, the levels of serum inflammatory factors and hepatic tissue inflammatory factor mRNA expression were significantly reduced, likely due to the anti-inflammatory phenotype induced by exosomes in macrophages. The above conclusion suggests that SCAPs-exosomes can improve NASH.

The Value of Left Internal Mammary Artery Flow Velocity in Predicting the Prognosis of Patients After Coronary Artery Bypass Grafting.

Background: The purpose of this study was to explore the value of the left internal mammary artery flow velocity (LIMAV) measured by ultrasound before coronary artery bypass grafting (CABG) in predicting the prognosis of patients after left internal mammary artery (LIMA) bypass grafting. Methods: One hundred and four patients who underwent CABG with LIMA as the bridge vessel in the cardiovascular surgery department of our hospital between May 2018 and June 2019 were selected. All patients underwent transthoracic Doppler ultrasonography to measure LIMAV preoperatively. Intraoperatively, mean graft flow (MGF) and pulsatility index (PI) of the LIMA bridge were measured using transit time flow measurement (TTFM). The primary endpoint event in this study was cardiac death within 18 months after surgery. Results: The Cox survival analysis showed that the MGF, the LIMAV and left ventricular ejection fraction (LVEF) were risk factors for death after CABG. The cut-offs of MGF, LIMAV and LVEF for the prediction of death after CABG were ≤ 14 mL/min (area under the curve (AUC): 0.830; sensitivity: 100%; specificity: 65.6%), ≤ 60 cm/s (AUC: 0.759; sensitivity: 65.5%; specificity: 85.3%), and ≤ 44% (AUC: 0.724; sensitivity: 50%; specificity: 88.5%), respectively. Compared with the use of MGF, MGF + LIMAV, combination of the MGF + LIMAV + LVEF (AUC: 0.929; sensitivity: 100%; specificity: 81.1%) resulted in a stronger predictive value (MGF vs. MGF + LIMAV + LVEF: P = 0.02). Conclusion: LIMAV measured by preoperative transthoracic ultrasound combined with intraoperative MGF and LVEF may have a greater value in predicting patients' risk of cardiac death after CABG.

Structural Characterization and Immunomodulatory Activity of a Mannose-Rich Polysaccharide Isolated from Bifidobacterium breve H4-2.

In this study, a novel homogeneous mannose-rich polysaccharide named EPS-1 from the fermentation broth of Bifidobacterium breve H4-2 was isolated and purified by anion exchange column chromatography and gel column chromatography. The primary structure of EPS-1 was analyzed by high-performance liquid chromatography, Fourier-transform infrared spectroscopy, gas chromatography-mass spectrometry, and nuclear magnetic resonance. The results indicated that EPS-1 had typical functional groups of polysaccharides. EPS-1 with an average molecular weight of 3.99 × 104 Da was mainly composed of mannose (89.65%) and glucose (5.84%). The backbone of EPS-1 was →2,6)-α-d-Manp-(1→2)-α-d-Manp-(1→2,6)-α-d-Manp-(1→2)-α-d-Manp-(1→2,6)-α-d-Manp-(1→6)-α-d-Glcp-(1→ simultaneously containing two kinds of branched chains (α-d-Manp-(1→3)-α-d-Manp-(1→ and α-d-Manp-(1→). Besides, EPS-1 had a triple-helical conformation and exhibited excellent thermal stability. Moreover, the immunomodulatory activity of EPS-1 was evaluated by RAW 264.7 cells. Results indicated that EPS-1 significantly enhanced the viability of RAW 264.7 cells. EPS-1 could also be recognized by toll-like receptor 4, thereby activating the nuclear factors-κB (NF-κB) signaling pathway, promoting phosphorylation of related nuclear transcription factors, improving cell phagocytic activity, and promoting the secretion of NO, IL-6, IL-1ß, and TNF-α. Thus, EPS-1 could activate the TLR4-NF-κB signaling pathway to emerge immunomodulatory activity on macrophages. The above results indicate that EPS-1 can serve as a potential immune-stimulating polysaccharide.

The nonautophagic functions of autophagy-related proteins.

ABBREVIATIONS: ATG: autophagy related; BECN1: beclin 1; cAMP: cyclic adenosine monophosphate; dsDNA: double-stranded DNA; EMT: epithelial-mesenchymal transition; IFN: interferon; ISCs: intestinal stem cells; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK/JNK: mitogen-activated protein kinase/c-Jun N-terminal kinases; MTOR: mechanistic target of rapamycin kinase; STING1: stimulator of interferon response cGAMP interactor 1; UVRAG: UV radiation resistance associated; VPS: vacuolar protein sorting.

Schisandrin B, a potential GLP-1R agonist, exerts anti-diabetic effects by stimulating insulin secretion.

Diabetes mellitus is a metabolic disease that is characterized by elevated blood sugar. Although glucagon-like peptide-1 receptor agonists (GLP-1RA) lower blood glucose in a glucose-dependent manner, most of them are macromolecule polypeptides. Macromolecular peptides are relatively expensive and inconvenient compared with small molecules. Therefore, this study sought to identify the small molecules binding to GLP-1R via cell membrane chromatography (CMC), confirm their agonistic activity, and further study its beneficial effects in a mouse model of type 2 diabetes mellitus (T2DM) induced by a combination of high-fat diet and streptozotocin. We used CMC, calcium imaging and molecular docking techniques to screen and identify the potential small molecule Schisandrin B (Sch B), which exhibits a strong binding effect to GLP-1R, from the small molecule library of traditional Chinese medicine. Through in-vitro experiments, we found that Sch B stimulated insulin secretion in ß-TC-6 cells, while GLP-1R antagonist Exendin9-39, adenylate cyclase inhibitor SQ22536, and protein kinase A (PKA) inhibitor H89 could significantly inhibit the insulin secretion induced by Sch B. In vivo, Sch B significantly improved fasting blood glucose levels, intraperitoneal glucose tolerance test damage, and the status of pancreatic tissue damage, and reduced serum insulin levels, total cholesterol, triglyceride and low density lipoprotein in T2DM mice. These results indicate that Sch B alleviates T2DM by promoting insulin release through the GLP-1R/cAMP/PKA signaling pathway, suggesting that Sch B may be a potential GLP-1RA, which is expected to provide a new therapeutic strategy for the prevention and treatment of T2DM.

Factors associated with persistent positive in HBV DNA level in patients with chronic Hepatitis B receiving entecavir treatment.

Introduction: The clinical significance of persistent positive in Hepatitis B Virus (HBV) DNA level in patients receiving antiviral therapy is not well known. We investigated factors associated with persistent viremia (PV) in patients with chronic hepatitis B (CHB) given 78-week entecavir. Methods: A total of 394 treatment-naïve CHB patients who had undergone liver biopsy at baseline and week 78 of treatment were analyzed in this prospective multicentre study. We identified patients with PV (above the lower limit of quantification, 20 IU/ml) after 78 weeks of entecavir therapy. Stepwise, forward, multivariate regression analyses of specified baseline parameters were apllied to identify factors associated with PV. Futhermore, we assessed the incidence of hepatocellular carcinoma (HCC) in all patients using models of the risk of HCC development. Results: Of the 394 patients, 90 (22.8%) still with PV after 78-week antiviral treatment. Factors associated significantly with PV (vs complete virological response, CVR) were HBV DNA level ≥8 log10 IU/mL (OR, 3.727; 95% CI, 1.851-7.505; P < 0.001), Anti-HBc level < 3 log10 IU/mL (OR, 2.384; 95% CI, 1.223-4.645; P=0.011), and HBeAg seropositivity (OR, 2.871; 95% CI, 1.563-5.272; P < 0.001). Patients with PV were less likely to have fibrosis progression and HCC development than those with the CVR. Of the 11 HBeAg-positive patients with HBV DNA level ≥8 log10 IU/mL and Anti-HBc level < 3 log10 IU/mL at baseline, 9 (81.8%) had persistent positivity in HBV DNA level and 0 had fibrosis progression at week 78 of treatment. Discussion: In conclusion, HBV DNA level ≥8 log10 IU/mL, Anti-HBc level < 3 log10 IU/mL and HBeAg seropositivity at baseline contribute to PV in patients with CHB receiving 78-week antiviral treatment. In addition, the rate of fibrosis progression and the risk of HCC development in patients with PV were kept low. The complete protocol for the clinical trial has been registered at clinicaltrials.gov (NCT01962155 and NCT03568578).

Novel, high accuracy models for hepatocellular carcinoma prediction based on longitudinal data and cell-free DNA signatures.

BACKGROUND & AIMS: Current hepatocellular carcinoma (HCC) risk scores do not reflect changes in HCC risk resulting from liver disease progression/regression over time. We aimed to develop and validate two novel prediction models using multivariate longitudinal data, with or without cell-free DNA (cfDNA) signatures. METHODS: A total of 13,728 patients from two nationwide multicenter prospective observational cohorts, the majority of whom had chronic hepatitis B, were enrolled. aMAP score, as one of the most promising HCC prediction models, was evaluated for each patient. Low-pass whole-genome sequencing was used to derive multi-modal cfDNA fragmentomics features. A longitudinal discriminant analysis algorithm was used to model longitudinal profiles of patient biomarkers and estimate the risk of HCC development. RESULTS: We developed and externally validated two novel HCC prediction models with a greater accuracy, termed aMAP-2 and aMAP-2 Plus scores. The aMAP-2 score, calculated with longitudinal data on the aMAP score and alpha-fetoprotein values during an up to 8-year follow-up, performed superbly in the training and external validation cohorts (AUC 0.83-0.84). The aMAP-2 score showed further improvement and accurately divided aMAP-defined high-risk patients into two groups with 5-year cumulative HCC incidences of 23.4% and 4.1%, respectively (p = 0.0065). The aMAP-2 Plus score, which incorporates cfDNA signatures (nucleosome, fragment and motif scores), optimized the prediction of HCC development, especially for patients with cirrhosis (AUC 0.85-0.89). Importantly, the stepwise approach (aMAP -> aMAP-2 -> aMAP-2 Plus) stratified patients with cirrhosis into two groups, comprising 90% and 10% of the cohort, with an annual HCC incidence of 0.8% and 12.5%, respectively (p <0.0001). CONCLUSIONS: aMAP-2 and aMAP-2 Plus scores are highly accurate in predicting HCC. The stepwise application of aMAP scores provides an improved enrichment strategy, identifying patients at a high risk of HCC, which could effectively guide individualized HCC surveillance. IMPACT AND IMPLICATIONS: In this multicenter nationwide cohort study, we developed and externally validated two novel hepatocellular carcinoma (HCC) risk prediction models (called aMAP-2 and aMAP-2 Plus scores), using longitudinal discriminant analysis algorithm and longitudinal data (i.e., aMAP and alpha-fetoprotein) with or without the addition of cell-free DNA signatures, based on 13,728 patients from 61 centers across mainland China. Our findings demonstrated that the performance of aMAP-2 and aMAP-2 Plus scores was markedly better than the original aMAP score, and any other existing HCC risk scores across all subsets, especially for patients with cirrhosis. More importantly, the stepwise application of aMAP scores (aMAP -> aMAP-2 -> aMAP-2 Plus) provides an improved enrichment strategy, identifying patients at high risk of HCC, which could effectively guide individualized HCC surveillance.

Discovery of nontriterpenoids from the rot roots of Panax notoginseng with cytotoxicity and their molecular docking study and experimental validation.

Panax notoginseng (PN) is a well-known traditional Chinese medicine, with dammarane-type triterpenoid saponins characterized as major component and active ingredients, together with amino acids, flavonoids, polysaccharides, and polyacetylenes. The roots of PN are susceptible to root rot disease, which causes a huge loss and changes in the chemical components of this precious resource. In this study, sub-fractions of rot PN root extracts were preliminarily found to have admirable cytotoxicity on two human cancer cells. Further bioassay-guided isolation discovered nine new non-triterpenoids, including two novel N-methylacetamido-1-oxotetrahydropyrimidine alkaloids (1, 2), five 2H-furanones or 2H-pyranones (3-7), and two polyacetylenic alcohols (8, 9). Their structures were illuminated by extensive spectroscopic data, calculated ECD, and X-ray diffraction analysis. Among them, 3-7 were considered to be transformed from panaxatriol through the intermediates (8, 9). The new alkaloids (1, 2) displayed noteworthy cytotoxicity against five human cancer cells with IC50 values ranging from 14 to 24 µM. In silico target prediction and molecular docking studies showed that 1 and 2 may interact with EGFR, and were verified by the experimental inhibitory effect on EGFR tyrosine kinase.

Erythropoietin ameliorates cognitive dysfunction in mice with type 2 diabetes mellitus via inhibiting iron overload and ferroptosis.

Type 2 diabetes mellitus (T2DM) is strongly associated with an increased risk of developing cognitive dysfunction. Numerous studies have indicated that erythropoietin (EPO) has neurotrophic effects. Ferroptosis has been reported to be associated with diabetic cognitive dysfunction. However, the impact of EPO on T2DM-associated cognitive dysfunction and its protective mechanism remain unclear. To evaluate the effects of EPO on diabetes-associated cognitive dysfunction, we constructed a T2DM mouse model and found that EPO not only decreased fasting blood glucose but also ameliorated hippocampal damage in the brain. The Morris water maze test indicated that EPO improved cognitive impairments in diabetic mice. Moreover, a ferroptosis inhibitor improved cognitive dysfunction in mice with T2DM in vivo. Furthermore, a ferroptosis inhibitor, but not other cell death inhibitors, mostly rescued high-glucose damaged PC12 cell viability. EPO had a similar effect as the ferroptosis inhibitor, which increased cell viability in the presence of a ferroptosis inducer. In addition, EPO reduced lipid peroxidation, iron levels, and regulated ferroptosis-related expression of proteins in vivo and in vitro. These findings indicate that EPO ameliorates T2DM-associated cognitive dysfunction, which might be related to decreasing iron overload and inhibiting ferroptosis.

An-Luo-Hua-Xian Pill Improves the Regression of Liver Fibrosis in Chronic Hepatitis B Patients Treated with Entecavir.

Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.

Hydronidone for the Treatment of Liver Fibrosis Related to Chronic Hepatitis B: A Phase 2 Randomized Controlled Trial.

BACKGROUND & AIMS: Hepatitis B virus infection frequently leads to liver fibrosis and is the leading cause of hepatocellular carcinoma and cirrhosis in Asia Pacific. Pirfenidone is approved by the United States Food and Drug Administration for treatment of idiopathic pulmonary fibrosis, and hydronidone is a novel structural modification of pirfenidone with the aim of reducing hepatoxicity. We aimed to investigate the safety and efficacy of hydronidone in patients with chronic hepatitis B (CHB)-associated liver fibrosis. METHODS: This was a 52-week multicenter, randomized, double-blind, placebo-controlled, phase II study at 8 centers in China. Patients with CHB with biopsied documented liver fibrosis were eligible and were randomly assigned into receiving daily placebo or hydronidone orally (180 mg/day, 270 mg/day, or 360 mg/day). All enrolled subjects also received entecavir 0.5 mg/day. A second liver biopsy was performed at week 52. The primary endpoint was defined as fibrosis improvement (reduction of at least 1 Ishak score at week 52 of treatment). RESULTS: From June 25, 2015, to September 5, 2019, 168 patients with CHB and liver fibrosis met the inclusion/exclusion criteria and were subsequently randomized, 43 in the placebo group and 125 in the hydronidone groups (42 in the 180-mg group, 42 in the 270-mg group, and 41 in the 360-mg group). The fibrosis improvement endpoint was achieved by 11 patients (25.6%) in the placebo group and 17 patients (40.5%) in the 180-mg group (P = .12), 23 patients (54.8%) in the 270-mg group (P = .006), and 18 patients (43.90%) in the 360-mg group (P = .08). The improvement rate was 58 of 125 (46.4%) in the combined hydronidone group (P = .014). The overall safety profile and incidence of serious adverse events were similar among the groups. CONCLUSIONS: Hydronidone plus entecavir showed clinically significant histological improvement of liver fibrosis in patients with CHB, and the dose of 270 mg showed the best efficacy of fibrosis regression. Further studies are required to assess the long-term effectiveness of hydronidone in regression of hepatic fibrosis. CLINICALTRIALS: gov number, NCT02499562.

Effects of Lycopene Attenuating Injuries in Ischemia and Reperfusion.

Tissue and organ ischemia can lead to cell trauma, tissue necrosis, irreversible damage, and death. While intended to reverse ischemia, reperfusion can further aggravate an ischemic injury (ischemia-reperfusion injury, I/R injury) through a range of pathologic processes. An I/R injury to one organ can also harm other organs, leading to systemic multiorgan failure. A type of carotenoid, lycopene, has been shown to treat and prevent many diseases (e.g., rheumatoid arthritis, cancer, diabetes, osteoporosis, male infertility, neurodegenerative diseases, and cardiovascular disease), making it a hot research topic in health care. Some recent researches have suggested that lycopene can evidently ameliorate ischemic and I/R injuries to many organs, but few clinical studies are available. Therefore, it is essential to review the effects of lycopene on ischemic and I/R injuries to different organs, which may help further research into its potential clinical applications.

Prevalence and clinical characteristics of autoimmune liver disease in hospitalized patients with cirrhosis and acute decompensation in China.

BACKGROUND: Autoimmune liver disease (AILD) has been considered a relatively uncommon disease in China, epidemiological data for AILD in patients with cirrhosis and acute decompensation (AD) is sparse. AIM: To investigate the prevalence, outcome and risk factors for AILD in cirrhotic patients complicated with AD in China. METHODS: We collected data from patients with cirrhosis and AD from two prospective, multicenter cohorts in hepatitis B virus endemic areas. Patients were regularly followed up at the end of 28-d, 90-d and 365-d, or until death or liver transplantation (LT). The primary outcome in this study was 90-d LT-free mortality. Acute-on-chronic liver failure (ACLF) was assessed on admission and during 28-d hospitalization, according to the diagnostic criteria of the European Association for the Study of the Liver (EASL). Risk factors for death were analyzed with logistic regression model. RESULTS: In patients with cirrhosis and AD, the overall prevalence of AILD was 9.3% (242/2597). Prevalence of ACLF was significantly lower in AILD cases (14%) than those with all etiology groups with cirrhosis and AD (22.8%) (P < 0.001). Among 242 enrolled AILD patients, the prevalence rates of primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and PBC-AIH overlap syndrome (PBC/AIH) were 50.8%, 28.5% and 12.0%, respectively. In ACLF patients, the proportions of PBC, AIH and PBC/AIH were 41.2%, 29.4% and 20.6%. 28-d and 90-d mortality were 43.8% and 80.0% in AILD-related ACLF. The etiology of AILD had no significant impact on 28-d, 90-d or 365-d LT-free mortality in patients with cirrhosis and AD in both univariate and multivariate analysis. Total bilirubin (TB), hepatic encephalopathy (HE) and blood urea nitrogen (BUN) were independent risk factors for 90-d LT-free mortality in multivariate analysis. The development of ACLF during hospitalization only independently correlated to TB and international normalized ratio. CONCLUSION: AILD was not rare in hospitalized patients with cirrhosis and AD in China, among which PBC was the most common etiology. 90-d LT-free mortality were independently associated with TB, HE and BUN.

Effects of Genistein on Common Kidney Diseases.

Genistein is a naturally occurring phytoestrogen (soy or soybean products) that is classified as an isoflavone, and its structure is similar to that of endogenous estrogens; therefore, genistein can exert an estrogen-like effect via estrogen receptors. Additionally, genistein is a tyrosine kinase inhibitor, which enables it to block abnormal cell growth and proliferation signals through the inhibition of tyrosine kinase. Genistein is also an angiogenesis inhibitor and an antioxidant. Genistein has effects on kidney cells, some of the kidney's physiological functions, and a variety of kidney diseases. First, genistein exerts a protective effect on normal cells by reducing the inflammatory response, inhibiting apoptosis, inhibiting oxidative stress, inhibiting remodeling, etc., but after cell injury, the protective effect of genistein decreases or even has the opposite effect. Second, genistein can regulate renin intake to maintain blood pressure balance, regulate calcium uptake to regulate Ca2+ and Pi balances, and reduce vasodilation to promote diuresis. Third, genistein has beneficial effects on a variety of kidney diseases (including acute kidney disease, kidney cancer, and different chronic kidney diseases), such as reducing symptoms, delaying disease progression, and improving prognosis. Therefore, this paper reviews animal and human studies on the protective effects of genistein on the kidney in vivo and in vitro to provide a reference for clinical research in the future.

Tenofovir is superior to entecavir in reducing HCC for patients with HBV-related compensated cirrhosis at high HCC risk scores.

Background: Both tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are known to reduce the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to compare the difference in HCC risk reduction between TDF and ETV in treatment-naïve patients with CHB-related compensated cirrhosis. Methods: Patients with compensated cirrhosis initially treated with TDF or ETV at nine Chinese hospitals between June 2014 and March 2021 were enrolled in this retrospective study. The cumulative HCC incidence rates for the two drugs were compared for the entire cohort, and a subgroup analysis was performed according to the HCC risk scores. Propensity score matching (PSM) was used to control confounding biases. Results: The analysis included 1453 patients (TDF group, n = 188; ETV group, n = 1265). Ninety-five patients developed HCC, with a median follow-up period of 26.1 months. The 3-year HCC incidence was 2.0% in the TDF group and 7.5% in the ETV group (log-rank p = 0.005). TDF treatment was associated with a lower risk of HCC than ETV treatment [hazard ratio (HR) = 0.222, 95% confidence interval (CI), 0.070-0.702, p = 0.010] but was similar after PSM (HR = 0.483, 95% CI, 0.144-1.626, p = 0.240; log-rank p = 0.230). However, subgroup analysis showed that the cumulative HCC incidence was lower in the TDF group than in the ETV group among patients with a modified PAGE-B score (mPAGE-B) ⩾9, either before or after PSM (log-rank p = 0.048 and p = 0.023, respectively). Conclusion: Among patients with an mPAGE-B score ⩾9, TDF is associated with a lower HCC incidence than ETV in patients with CHB-related compensated cirrhosis.

Intestinal microecology in mice bearing diethylnitrosamine-induced primary hepatocellular carcinoma.

OBJECTIVE: To explore the characteristics of intestinal microecology in hepatocellular carcinoma (HCC) model mice. METHODS: C57BL/6 male mice aged 2 weeks were divided into normal control group and HCC model group. Mice in HCC model group were exposed to a single intraperitoneal injection of diethylnitrosamine (DEN) 2 weeks after birth; the surviving mice were intraperitoneally injected with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), once every 2 weeks for 8 times starting from the 4 th week after birth. Mice in each group were randomly selected and sacrificed at 10 th, 18 th and 32 nd weeks after birth, respectively, the liver tissue samples were obtained for histopathological examination. At the 32 nd week, all mice in both groups were sacrificed and the feces samples were collected under sterile conditions right before the sacrifice. The feces samples were sequenced for the V3-V4 hypervariable regions of the 16S rRNA gene, and the species abundance, flora diversity and phenotype, as well as flora correlation and functional prediction were analyzed. RESULTS: Alpha diversity analysis showed that all Good's coverage reached the maximum value of 1.00, and the differences in the Observed features, Chao1 index, Shannon index and Simpson index of the intestinal flora of mice between normal control group and HCC model group were all statistically significant (all P<0.05). Beta diversity analysis showed that PCoA based on weighted or unweighted Unifrac distances all yielded R>0, confirming that the intra-group differences of the samples were less than the inter-group differences; the trend of separation between the two groups was significant ( P<0.05). Bacteroidetes, Firmicutes, Actinobacteria and Patescibacteria were the dominant taxa at the phylum level in both normal control group and HCC model group. However, compared with normal control group, the abundance of Bacteroidetes in HCC model group was significantly decreased ( P<0.01), while the abundance of Patescibacteria was significantly increased ( P<0.05). Moreover, the dominant taxa at the genus level in normal control group mainly included Muribaculaceae_unclassified, Paramuribaculum, Muribaculum, Lachnospiraceae_NK4A 136 group, Olsenella. The dominant taxa at the genus level in HCC model group mainly included Akkermansia, Dubosiella, Muribaculaceae_unclassified, Lachnospiraceae_NK4A 136 group, Coriobacteriaceae_UCG-002. There were 30 genera with statistically significant differences in relative abundance at the genus level between the two groups (all P<0.05). LEfSe analysis of the intestinal flora of mice in the two groups revealed a total of 14 multi-level differential taxa (all P<0.05, LDA score>4.0), which were mainly enriched in Bacteroidetes. The enrichment of 10 differential taxa including Bacteroidetes, Bacteroidia, Bacteroidales, Muribaculaceae, etc. were found in normal control group, and the enrichment of 4 differential taxa including Dubosiella, Peptostreptococus, etc. were found in HCC model group. There were both positive and negative correlations between the dominant intestinal genera in normal control group (|rho|>0.5, P<0.05), while the correlations of the dominant intestinal genera in HCC model group, being less complex than that in normal control group, were all positive. The relative abundance of gram positive and mobile element containing in the intestinal flora of mice in HCC model group was significantly up-regulated compared with normal control group (both P<0.05), while that of gram negative ( P<0.05) and pathogenic potential ( P<0.05) was significantly down-regulated. The metabolic pathways of the intestinal flora in the two groups were significantly different. For instance, 18 metabolic pathways were enriched in normal control group (all P<0.005), including those related to energy metabolism, cell division, nucleotide metabolism, etc., while 12 metabolic pathways were enriched in HCC model group (all P<0.005), including those related to energy metabolism, amino acid metabolism, carbohydrate metabolism, etc. Conclusions: The amount of intestinal flora in DEN-induced primary HCC model mice decreased, and the composition, correlation, phenotype and function of the intestinal flora in mice were significantly altered. Bacteroidetes at the phylum level, as well as several microbial taxa at the genus level such as Muribaculaceae_unclassified, Muribaculum, Peptostreptococus and Dubosiella could be closely associated with DEN-induced primary HCC in mice.